Abstract

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Tyrosine kinases inhibitors (TKI) are small molecules that interfere with cell signalling and target selected malignancies. The concern associated with oral drugs is related to their low and unpredictable bioavailability. In the past years, several TKI have been introduced in oncology and the risk of serious drug-drug interactions is very important and deserves to be taken into consideration. It is difficult to find a concise tool to help oncologists with this matter and this could create issues in the daily clinic.

This article gives a brief overview of known or suspected interactions either with other drugs or foods. Oncologists should carefully review the concomitant medications for each patient in order to prevent any relevant interactions or to monitor them closely. 

Introduction

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Tyrosine kinases inhibitors (TKI) are small molecules, orally administered that interfere with cell signalling and allow target-specific treatment for selected malignancies. Patients’ preference for oral treatment is well known and from the medical perspective, although it could be perceived as an advantage, the concern is that oral drugs may have low and unpredictable bioavailability. This could be due to variable degradation in gastrointestinal system, intestinal P-glycoprotein and interaction with cytochrome P450 (CYP3A4) catalytic activity which varies as much as 10-fold among individuals.

In the past years, several TKI have been introduced in oncology. These agents are currently extensively used and serious drug-drug interactions are a high risk event.

This article gives a brief overview of known or suspected drug-drug interactions between TKI and other drugs. Most interactions are related to metabolism by cytochrome P450 isoenzymes, altered stomach pH and prolongation of the QTc interval. The data are presented in tables.

Oncologists should carefully review the concomitant medications for each patient in order to prevent any relevant interactions or to monitor closely them.

 

Cytochrome P450 and family

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Table 1: Cytochrome P450, family 3, subfamily A (CYP3A4/5) inhibitors and inducers

inhibitors		may increase plasma concentrations		inducers		may reduce plasma concentrations
strong		Ketoconazole Itraconazole Voriconazole	Avoid concomitant use or dose adjustment or monitoring	strong		Rifampicin Rifabutin Rifapentin	Avoid concomitant use or dose adjustment or monitoring
		Clarithromycin				Dexamethasone
		Atazanavir Indinavir Nefazodone Nelfinavir Ritonavir Saquinavir				Phenytoin Carbamazepine Phenobarbital Topiramate
		Nefazodone				Hypericum perforatum [St. John's wort])
Moderate		Diltiazem Verapamil Amiodarone		Unspecified potency		Modafinil
		Aprepitant				Capsaicin
		Bicalutamide				Pioglitazone Troglitazone
		Erythromycin
		Grapefruit
		Valerian
Weak		Valproic

QT interval

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Table 2: Drugs which prolong QT interval

Antisickness	Onsansetron Domperidone
Antidepressants	Fluoxetine Trazodone Citalopram
Antiarrhythmics	Flecainide Quinidine Procainamide Sotalol Amiodarone
Antifungal	Fluconazole Voriconazole
Hormonal therapy	Gosereline
Opioids	Methadone
B2 agonists	Salmeterol
Alpha-blockers	Alfuzosin
Antibiotics	Azithromycin Ciprofloxacin Clarithromycin Erythromycin
Antipsychotics	Chlorpromazine Haloperidol
Antimalarial	Chloroquine Quinine

CYP3A substrates

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Table 3: CYP3A substrates

Antifungals	Ketoconazole Itraconazole
Antibiotics	Clarithromycin Erythromycin
Antidepressants	Mirtazapine Venlafaxine Trazodone Sertraline Citalopram Norfluoxetine Amitryptiline
Antipsychotics	Haloperidol
Opioids	Buprenorphine Codeine Fentanyl Methadone Tramadol Alfentanil
Benzodiazepines and hypnotics	zopiclone alprazolam zolpidem midazolam diazepam
Statins	Atorvastatin Simvastatin
Calcium chanel blockers	nifedipine Diltiazem Verapamil
Antiemetics	aprepitant Domperidone ondansetron
Steroids	dexamethasone hydrocortisone
Proton pump inhibitor	Omeprazole
Antiplatelets	Clopidogrel
Beta agonists	Salmeterol
Stimulants	Caffeine
Protease inhibitors	Indinavir Ritonavir
H1 receptor antagonists	Chlorphenamine
PDE5 inhibitors	Sildenafil
antiarrhythmics	Amiodarone

P-glycoprotein (PgP)

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Table 4: Drugs and P-glycoprotein (PgP)

Substrates	Inhibitors	Inducers
Colchicine	Verapamil	Carbamazepine
Digoxin	Amiodarone	Rifampicin
Morphine	Clarithromycin	St John’s Wort
Indinavir	Erythromycin
	Ketoconazole
	Quinidine

Drugs interacting with CYP3A substrates, inhibitors, inducers and PgP

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Table 5: Drugs interacting with CYP3A substrates

 

Table 6:  Drug interactions with CYP3A inhibitors/inducers

 

Table 7: Drugs interacting with PgP substrates

Gastric pH

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Table 8: Interactions with pump inhibitors and antiacids

Anticoagulants

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Table 9: Interactions with anticoagulants

	Warfarin	Option
Axitinib	no interaction
Cabozantinib	no interaction
Crizotinib	no interaction
Dabrafenib	Reduce warfarin exposure	Close monitoring
Gefitinib	Increase risk of bleeding	Close monitoring
Everolimus	no interaction
Imatinib	Not to use	Low molecular weight heparin
Lenvatinib	no interaction
Lapatinib	no interaction
Regorafenib	Increase risk of bleeding	Close monitoring
Sorafenib	Low risk
Sunitinib	no interaction
Pazopanib	no interaction
Vandetanib	Possible interaction	Close monitoring Not to use dabigatran
Vemurafenib	Increase risk of bleeding	Close monitoring

Other interactions

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Table 10: Other interactions

	Increase	Decrease	No significant change
Levels of midazolam	Crizotinib	Vemurafenib	Regorafenib
	Everolimus		Sorafenib
	Lapatinib
	Pazopanib
Levels of oral contraception		Vemurafenib Lenvatinib??
Levels of statins	Imatinib		Everolimus
Atorvastatin	Regorafenib
Simvastatin	Pazopanib
Bisphosphonates	Cabozantinib
	Sunitinib
Metformin	Vandetanib
Digoxin	Crizotinib		Regorafenib
	Lapatinib
	Sorafenib
	Vandetanib
	Vemurafenib
Dextromethorphan	Pazopanib		Sorafenib

Method of administration

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Table 11: Method of administration

	As a whole	With food	Without food	Water	Other options
Axitinib	X	X	X	X
Cabozantinib	X		X	X	2 h before and 1 h after
Crizotinib	X	X	X	X
Dabrafenib	X			X	1 h before or 2 after a meal
Gefitinib	X			X	Dissolve in half glass of water (20 min),  drink immediately. Add more water and drink
Everolimus	X	X	X	X
Imatinib	X	X		X
Lenvatinib				X/apple juice	In 1 tablespoon for 10 min, stir for 3 min and drink
Lapatinib	X		X		1 h before or after a meal
Regorafenib	X	X Low fat		X
Sorafenib	X	X Low fat	X	X
Sunitinib	X	X	X	X
Pazopanib	X		X		1 h before or 2 h after
Trametinib	X			X	1 h before or 2 after a meal
Vandetanib	X		X	X	disperse in half glass of water Before or after a meal
Vemurafenib	X			X

Conclusion

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In the past decade, many TKI have been introduced in oncology as targeted therapies against different malignancies. Although they seem to be well tolerated, the risk of serious interactions exists and it is the oncologist's responsibility to know these in order to prevent any relevant issues, such as toxicities or lack of effectiveness due to reduced bioavailability.

This brief summary presented in Tables form, pretends to be an easy tool to consult in the routine practice to help doctors make quick decisions and manage correctly these medications.

Acknowledgements

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I thank all those who have always challenged me; I appreciate their effort to make me brave enough to stand up for myself

Source(s) of Funding

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N/A

Competing Interests

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None